Urothelial ATP Signaling and Diabetic Bladder Dysfunction

尿路上皮 ATP 信号转导和糖尿病性膀胱功能障碍

• 批准号: 8069339
• 负责人: SYLVIA OTTILIE SUADICANI
• 金额: $ 28.47万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069339
• 关键词: Animals; Biochemistry; Bladder; Bladder Diseases; Bladder Dysfunction; Bladder Urothelium; Communication; Development; Diabetes Mellitus; Dinoprostone; Fiber; Goals; Health; Image; In Vitro; Lead; Mediating; Membrane; Micturition Reflex; Molecular Biology; Motor; Myofibroblast; Nerve Fibers; Pathway interactions; Pharmacology; Physiology; Play; Prostaglandins; Proteins; Purinoceptor; Relative (related person); Role; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle; Smooth Muscle Myocytes; Streptozocin; Symptoms; System; Testing; Up-Regulation; Urodynamics; Urothelial Cell; Urothelium; afferent nerve; base; design; detrusor muscle; diabetic; diabetic rat; intercellular communication; new therapeutic target; novel; receptor; research study; response

DESCRIPTION (provided by applicant): ATP plays important roles in the sensory and motor functions of the urinary bladder. ATP released from parasympathetic fibers can excite the detrusor muscle, and ATP released from the urothelium in response to bladder distension can indirectly modulate detrusor contractility by activating afferent fibers, stimulating suburothelial myofibroblasts and inducing release of other signaling molecules from the urothelium. Pathological conditions can increase the purinergic component of the neurogenic detrusor contraction and also augment urothelial ATP release. In diabetes various urodynamic abnormalities can develop, including increased bladder activity. We have proposed that increased sensitivity of diabetic bladders to purinergic stimulation was related to upregulation of specific purinergic receptor (P2R) subtypes in the detrusor muscle, and that amplification of ATP signaling would directly contribute to the development of bladder overactivity in diabetes. Based on recent findings we have now evidence that ATP signaling in also amplified in the diabetic bladder urothelium. Expression of P2Rs, particularly the P2X7R and P2X3R subtypes, is markedly increased in the urothelium of STZ-diabetic rat bladders and responses to ATP are higher in STZ-diabetic urothelial cells. These findings combined with demonstrations that P2X7R activation can induce release of both ATP and prostaglandin (PGE2), suggest that not only the sensitivity to ATP but also ATP and PGE2 release from urothelial cells is increased in diabetic bladders. In this context, afferent signaling from the bladder as well as ability of urothelial cells, suburothelial myofibroblast and smooth muscle cells to communicate would be significantly enhanced and likely contribute to increase bladder activity in diabetes. To test the hypotheses that diabetes increases urothelial ATP signaling and communication between bladder compartments, and that enhanced ATP signaling within and from the bladder contributes to the development of bladder dysfunction in diabetes we will use a combination of molecular biology, biochemistry, pharmacology, in vitro subcellular imaging and whole animal physiology approaches. These studies are expected to lead to novel understanding of the interplay among specific membrane receptors and channel proteins involved in intercellular signaling between urothelium and bladder smooth muscle, and reveal novel therapeutic targets and strategies to ameliorate the symptoms of bladder dysfunction in diabetes. PUBLIC HEALTH RELEVANCE: The studies proposed in this RO1 application are expected to further our understanding of the interactions between the bladder urothelial, suburothelial and smooth muscle compartments and of how changes in the expression of main components of the urothelial ATP signaling contribute to the development of bladder dysfunction in diabetes.

描述（申请人提供）：ATP在膀胱的感觉和运动功能中起重要作用。副交感神经纤维释放的ATP可刺激逼尿肌，尿路上皮响应膀胱扩张释放的ATP可通过激活传入纤维、刺激上皮下肌成纤维细胞和诱导尿路上皮释放其他信号分子间接调节逼尿肌收缩。病理条件可增加神经源性逼尿肌收缩的嘌呤能成分，也可增加尿路上皮ATP释放。糖尿病患者可出现各种尿动力学异常，包括膀胱活动增加。我们提出糖尿病膀胱对嘌呤能刺激的敏感性增加与逼尿肌中特定嘌呤能受体（P2R）亚型的上调有关，ATP信号的放大将直接促进糖尿病膀胱过度活动的发展。根据最近的发现，我们现在有证据表明ATP信号在糖尿病膀胱尿路上皮中也被放大。P2Rs的表达，特别是P2X7R和P2X3R亚型，在stz -糖尿病大鼠膀胱尿路上皮中显著增加，对ATP的反应在stz -糖尿病尿路上皮细胞中更高。这些发现结合P2X7R激活可以诱导ATP和前列腺素（PGE2）的释放，表明糖尿病膀胱中尿路上皮细胞不仅对ATP的敏感性增加，而且ATP和PGE2的释放也增加。在这种情况下，来自膀胱的传入信号以及尿路上皮细胞、上皮下肌成纤维细胞和平滑肌细胞的交流能力将显著增强，并可能导致糖尿病患者膀胱活动增加。为了验证糖尿病增加尿路上皮ATP信号传导和膀胱间室之间通信的假设，以及膀胱内和膀胱外ATP信号传导的增强有助于糖尿病膀胱功能障碍的发展，我们将结合分子生物学、生物化学、药理学、体外亚细胞成像和全动物生理学方法。这些研究有望导致对尿路上皮和膀胱平滑肌细胞间信号传导的特异性膜受体和通道蛋白之间相互作用的新认识，并揭示改善糖尿病膀胱功能障碍症状的新治疗靶点和策略。公共卫生相关性：本RO1应用中提出的研究有望进一步加深我们对膀胱尿路上皮、尿路上皮下和平滑肌间室之间相互作用的理解，以及尿路上皮ATP信号主要成分表达的变化如何促进糖尿病患者膀胱功能障碍的发展。